Project A: Hormone Therapy and Risk of Ovarian Cancer. Since 2001, three observational studies have reported a significantly increased risk of invasive epithelial ovarian cancer (IEOC) in association with use of hormone therapy (HT). A 2003 report from the Women's Health Initiative supports this finding. Our combined analysis of 10 observational studies provides strong evidence that risk of IEOC is increased with the use of unopposed estrogen therapy (ET) but the extent of the risk is uncertain. While our analysis also suggests that risk of IEOC may be increased in association with use of estrogen-progestin therapy (EPT), this conclusion is based on fewer data. Additional data are needed to estimate precisely the duration-response relationship for ET and EPT. There is also a need to characterize risk patterns by dose and temporal factors, by other risk factors (e.g., body size), and by histology of IEOC. If HT increases the risk of IEOC, the mechanisms of action are not well-understood. We propose a large population-based case-control study of IEOC in Los Angeles County (LAC) consisting of approximately 952 incident cases and an equal number of control subjects between 45 and 79 years of age. Data from the proposed study will be combined with an additional 986 IEOC and 1,121 controls from three other population-based case-control studies of IEOC we have conducted in LAC during the last decade. In addition to obtaining complete information on HT use, DNA specimens will be obtained from subjects in this proposed study (DNAsamples are already available from 653 cases and 862 controls in our previous studies). The availability of DNA samples on approximately 1,510 IEOC cases and 1,719 control subjects will allow us to conduct a comprehensive investigation of variations in genes, as measured by single nucleotide polymorphisms and haplotypes, involved in HT metabolism, transport or action. We will investigate whether the genetic variants exert independent effects on risk of IEOC and/or modify the HT-IEOC association.